Idarucizumab, an investigational drug, rapidly and
completely neutralizes the anticoagulant activity of dabigatran in most patients
who have serious bleeding or require an urgent procedure, according to an interim
analysis of the RE-VERSE AD trial published online June 22, 2015, ahead of
print in the New England Journal of
Medicine.

“There were no safety concerns among the 90 patients
involved in this study—including patients who were given idarucizumab on
clinical grounds but were later found to have had normal results on clotting
tests at baseline,” say Charles V. Pollack Jr, MD, of Pennsylvania Hospital
(Philadelphia, PA), and colleagues.

In the ongoing, multicenter RE-VERSE AD trial, up to 300
patients who are taking the oral thrombin inhibitor dabigatran (Pradaxa,
Boehringer Ingelheim) will receive 5 g of IV idarucizumab (Boehringer
Ingelheim) if they either:

or need surgery or other invasive procedures
that cannot be delayed at least 8 hours for which normal hemostasis is required
(group B).

Idarucizumab is a humanized monoclonal antibody fragment
with high affinity for dabigatran that selectively and immediately neutralizes
its anticoagulant activity.

For the interim analysis, the investigators looked at 90
patients (median age 76.5 years; 56% men; median creatinine clearance 58
mL/min) who were enrolled from June 2014 through February 2015. There were51 patients
in group A (16 of them hemodynamically unstable) and 39 in group B. More than
90% were receiving dabigatran for stroke prevention in the context of
nonvalvular A-fib. The median patient-reported time from last dabigatran dose
was 15.4 hours.

At study entry, 22 patients were determined by the dilute
thrombin time test to have normal clotting and were excluded, leaving 68
patients—40 from group A and 28 from group B—for analysis of efficacy.

Quick Reversal
Confirmed

The median maximum percentage reversal of anticoagulation
(primary endpoint) was 100% (95% CI 100-100) in groups A and B, as assessed by
both dilute thrombin time and ecarin clotting time. Reversal was evident soon after
the first of 2 equal idarucizumab infusions. Among the patients who could be
evaluated, dilute thrombin time was normalized in 98% of group A and 93% of
group B, while ecarin clotting time was normalized in 89% and 88%,
respectively. Similar results were seen with regard to activated
partial-thromboplastin time and thrombin time.

At baseline, the median plasma concentration of unbound
dabigatran was 84 ng/mL in group A and 76 ng/mL in group B. But after the
initial administration of idarucizumab, the concentration had fallen in all but
1 patient to below 20 ng/mL—a level that the authors say produces little or no
anticoagulant effect. At 4 hours, 83 of 86 patients had a concentration near
the lower limit of quantification, with only 2 having high concentrations.

Among the 35 patients in group A for whom hemostasis
could be ascertained, the metric was restored at a median of 11.4 hours. Among
the 36 patients in group B who underwent urgent procedures, normal hemostasis
was reported in 92%.

Overall, there were 18 deaths—9 in each group—with 10 due
to vascular causes, including 5 fatal bleeding events.

Thrombotic events occurred in 5
patients. Deep-vein thrombosis and pulmonary embolism were seen in 1 patient 2
days after treatment; the other events occurred more than 72 hours after
idarucizumab administration. None of the patients were receiving antithrombotic
therapy at the time.

A total of 21 patients (13 in group A and 8 in group B)
experienced serious adverse events. In addition to the deaths and thrombotic
events, these included GI hemorrhage in 2 patients and post-op wound infection,
delirium, right ventricular failure, and pulmonary edema in 1 patient each.

According to the authors, the 5-g dose ofidarucizumab was selected on the basis
of the highest range of plasma concentrations measured in the RE-LY trial. Though the
concentration of unbound dabigatran was reduced to nearly undetectable levels
in all but 1 patient immediately after treatment, the subsequent increases in
the anticoagulant concentration seen in some patients after 12 and 24 hours may
reflect the redistribution of extravascular dabigatran into the intravascular
compartment, they suggest. “It is uncertain whether patients with such a
response would benefit from additional idarucizumab,” the investigators add.

Lack of an
Effective Antidote Unnerving

In a telephone interview with TCTMD, Dr. Pollack said
concern over the lack of a reversal agent for the novel oral anticoagulants is
shared by many clinicians and emergency department (ED) doctors. Major bleeds
in patients on these drugs are uncommon, he commented, but when they occur,
they are “scary” to deal with.

In an accompanying editorial, Kenneth A. Bauer, MD, of
Beth Israel Deaconess Medical Center (Boston, MA), writes: “With the growing
use of direct oral anticoagulants, it would be advantageous to have reversal
agents that can rapidly and completely neutralize the anticoagulant activity of
the drug and restore normal hemostasis…. Given that there are no established
reversal strategies for the direct oral anticoagulants, it is appropriate to
undertake clinical trials of these agents without a control group.”

Assessment of
Clinical Benefit Hampered by Trial Design?

However, Dr. Bauer notes the absence of a control group makes
it difficult to assess the clinical benefit conferred by idarucizumab in
patients with dabigatran-related bleeding.

“Given that the half-life of dabigatran is 12 to 14 hours
if renal function is normal, how important is it to be able to neutralize the
anticoagulant activity of dabigatran rapidly in addition to providing
supportive care measures?” he asks. “[T]he location and size of the lesion
along with the coexisting conditions of the patient may have a greater effect
on prognosis than the ability to rapidly neutralize an anticoagulant that the
patient is taking,” he says.

Dr. Pollack defended the trial’s use of a surrogate,
pharmacodynamic primary endpoint. He explained that the study population of
mostly of A-fib patients, who are typically older and have multiple comorbidities,
is “just too heterogeneous a group to be able to power a study for clinical
outcomes.” Even so, he added, “I think our clinical outcomes are quite
impressive.”

Moreover, Dr. Bauer notes, nearly one-quarter of the
study population had “little or no circulating anticoagulant in their blood and
would not be expected to benefit from the administration of idarucizumab. Thus,
it will be useful to have activity measurements available for the various
direct oral anticoagulants in real time to help guide the treatment of such
patients and to prevent overutilization of what will surely be a costly
medication.”

Dr. Pollack agreed in principle but added that “in the
real world” the absence of real-time information on drug concentration is not
usually problematic. In fact, he noted, ED doctors reverse warfarin in patients
with an intracranial bleed before knowing their INR. Nonetheless, he added, “if
when we finish the study it turns out that we can get some guidance from
clotting assays, we will absolutely [take advantage of] that. But I think this
drug’s use will be driven by clinical assessment.”

Asked to describe an ideal reversal agent, Dr. Pollack
said it would need to provide safe, immediate, complete, and sustained reversal,
with no prothrombotic effect or allergic concerns—much like idarucizumab—but also
potentially neutralize multiple anticoagulants. “As an emergency physician, if
I had 1 reversal agent I could go to no matter what the patient was taking,
that might be an advantage.” However, he added, development of a universal
antidote is considerably less far along than that of idarucizumab.

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